Pendyala Lakshmi, Schwartz Gary, Smith Patrick, Zdanowicz Joseph, Murphy Michael, Hausheer Frederick
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Cancer Chemother Pharmacol. 2003 May;51(5):376-84. doi: 10.1007/s00280-003-0587-y. Epub 2003 Apr 8.
BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate) was evaluated in a phase I clinical trial with paclitaxel and cisplatin to assess the safety and potential efficacy for preventing or reducing cisplatin- and paclitaxel-induced toxicities. During this trial the effects of BNP7787 administration on the total concentrations (oxidized plus free) of cysteine, homocysteine and GSH in plasma, free and total GSH in WBC and rate of urinary excretion of cysteine were studied. The pharmacokinetics of ultrafilterable (free, non-protein bound) platinum were also determined after cisplatin (75 mg/m(2)) treatment which followed paclitaxel (175 mg/m(2)) and BNP7787 (8.2 to 27.6 g/m(2)).
Plasma thiols were measured by HPLC with fluorescence detection and platinum was measured by atomic absorption spectrophotometry.
BNP7787 administration produced a significant depletion of all plasma thiols in all the patients studied. Differences were noted in the kinetics of BNP7787-induced depletion of cysteine and other thiols. A significant depletion of cysteine occurred with a time lag of about 2 h after the end of BNP7787 infusion, while a reversible depletion of GSH and homocysteine occurred immediately following the start of BNP7787 infusion, with the plasma thiol/disulfide nadir corresponding to the end of infusion. The mean half-life of cysteine depletion following BNP7787 administration was 2.2 h, significantly longer than for homocysteine (0.23 h), or GSH (0.18 h; P<0.05 for both). A several-fold increase in the urinary excretion of cysteine occurred following BNP7787 administration in all patients. The BNP7787-induced thiol/disulfide depletion in plasma was not affected by cisplatin administration ( P>0.05). BNP7787 administration had no effect on the ultrafilterable platinum pharmacokinetics. The 2-h lag in the depletion of cysteine, the most abundant thiol in plasma, suggests that the process may be related to the formation of free mesna from BNP7787 and that increased levels of mesna are not in circulation until after 2 h after BNP7787 administration. No effect of BNP7787 was seen on the GSH concentration in WBC, possibly reflecting the inability of these cells to take up BNP7787.
The results suggest that BNP7787 has the potential to enhance cisplatin antitumor activity by depleting the reactive thiols in plasma.
在一项与紫杉醇和顺铂联合进行的I期临床试验中，对BNP7787（2,2'-二硫代双乙烷磺酸钠）进行了评估，以评估其预防或降低顺铂和紫杉醇诱导的毒性的安全性和潜在疗效。在该试验期间，研究了给予BNP7787对血浆中半胱氨酸、同型半胱氨酸和谷胱甘肽的总浓度（氧化型加游离型）、白细胞中游离和总谷胱甘肽以及半胱氨酸尿排泄率的影响。在紫杉醇（175mg/m²）和BNP7787（8.2至27.6g/m²）之后给予顺铂（75mg/m²）治疗后，还测定了可超滤（游离、非蛋白结合）铂的药代动力学。
血浆硫醇通过高效液相色谱荧光检测法测定，铂通过原子吸收分光光度法测定。
在所有研究患者中，给予BNP7787后所有血浆硫醇均显著减少。观察到BNP7787诱导的半胱氨酸和其他硫醇减少的动力学存在差异。BNP7787输注结束后约2小时出现半胱氨酸的显著减少，而在BNP7787输注开始后立即出现谷胱甘肽和同型半胱氨酸的可逆减少，血浆硫醇/二硫化物最低点对应于输注结束。BNP7787给药后半胱氨酸减少的平均半衰期为2.2小时，显著长于同型半胱氨酸（0.23小时）或谷胱甘肽（0.18小时；两者P<0.05）。所有患者在给予BNP7787后半胱氨酸尿排泄增加了几倍。顺铂给药对BNP7787诱导的血浆硫醇/二硫化物减少没有影响（P>0.05）。BNP7787给药对可超滤铂的药代动力学没有影响。血浆中最丰富的硫醇半胱氨酸减少存在2小时的延迟，这表明该过程可能与BNP7787形成游离美司钠有关，并且直到BNP7787给药后2小时后美司钠水平才在循环中升高。未观察到BNP7787对白细胞中谷胱甘肽浓度的影响，这可能反映了这些细胞无法摄取BNP7787。
结果表明，BNP7787有可能通过消耗血浆中的反应性硫醇来增强顺铂的抗肿瘤活性。
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